Silver(I) triflate-catalyzed protocol for the post-ugi synthesis of spiroindolines

A silver(I) triflate-catalyzed protocol for the post-Ugi synthesis of tetracyclic spiroindolines has been developed. The protocol worked best for indole-3-carbaldehyde-derived Ugi adducts obtained using anilines and 3-aryl propiolic acids. Thus, it is complementary to the previous cationic gold-catalyzed procedure that was developed for analogues Ugi substrates derived from aliphatic amines and 3-alkyl propiolic acids. Furthermore, we have demonstrated that under our new settings this domino Friedel-Crafts ipso cyclization / imine trapping process could be efficiently combined with the preceding four-component Ugi reaction into a two-step one-pot transformation

Programmed cell death 6 interacting protein (PDCD6IP) and Rabenosyn-5 (ZFYVE20) are potential urinary biomarkers for upper gastrointestinal cancer

PURPOSE: Cancer of the upper digestive tract (uGI) is a major contributor to cancer-related death worldwide. Due to a rise in occurrence, together with poor survival rates and a lack of diagnostic or prognostic clinical assays, there is a clear need to establish molecular biomarkers. EXPERIMENTAL DESIGN: Initial assessment was performed on urine samples from 60 control and 60 uGI cancer patients using MS to establish a peak pattern or fingerprint model, which was validated by a further set of 59 samples. RESULTS: We detected 86 cluster peaks by MS above frequency and detection thresholds. Statistical testing and model building resulted in a peak profiling model of five relevant peaks with 88% overall sensitivity and 91% specificity, and overall correctness of 90%. High-resolution MS of 40 samples in the 2-10 kDa range resulted in 646 identified proteins, and pattern matching identified four of the five model peaks within significant parameters, namely programmed cell death 6 interacting protein (PDCD6IP/Alix/AIP1), Rabenosyn-5 (ZFYVE20), protein S100A8, and protein S100A9, of which the first two were validated by Western blotting. CONCLUSIONS AND CLINICAL RELEVANCE: We demonstrate that MS analysis of human urine can identify lead biomarker candidates in uGI cancers, which makes this technique potentially useful in defining and consolidating biomarker patterns for uGI cancer screening

Frequency and clinical significance of histologic upper gastrointestinal tract findings in children with inflammatory bowel disease

Objective Assessment of the upper gastrointestinal tract (UGI) may enable more personalized treatment strategies in pediatric inflammatory bowel disease (IBD). However, data on the frequency and significance of these findings remain limited. Methods Data on 132 pediatric IBD patients with systematic UGI sampling were collected and the baseline characteristics and presence of complications compared between those with and without histological UGI findings. The control group comprised 162 children who received no diagnoses. Results Seventy-six children had ulcerative colitis (UC), 47 Crohn's disease (CD) and nine IBD unclassified. UGI findings were more common in IBD patients than controls (69.7% vs. 30.9%, respectively, p < .001), particularly in the stomach (62.1% vs. 16.8%; p < .001). Among IBD patients, findings were more common in CD than in UC (80.9% vs. 63.2%; p = .038), particularly in the duodenum (21.3% vs. 2.6%, p = .001). Four patients had UGI granulomas consistent with CD. Hypoalbuminemia (OR 3.22; 95% CI 1.18-8.79) and failure to thrive (2.82; 1.17-6.78) increased the likelihood of UGI findings in IBD. In CD, perianal morbidity was less common in those with than in those without UGI findings (13.2% vs. 44.4%; p = .032) whereas in UC, UGI findings increased the risk for co-morbidities (18.8% vs. 3.6%; p = .059). The long-term outcomes did not differ between patients with or without UGI findings. Conclusions Histologic UGI findings were more common in children with IBD than in children with no gastrointestinal diagnoses. In CD, UGI findings were more frequent than in UC, especially in the duodenum. In UC, UGI findings were associated with more complex disease.Peer reviewe

Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase

Uracil-DNA glycosylase (UDG) compromises the replication strategies of diverse viruses from unrelated lineages. Virally encoded proteins therefore exist to limit, inhibit or target UDG activity for proteolysis. Viral proteins targeting UDG, such as the bacteriophage proteins ugi, and p56, and the HIV-1 protein Vpr, share no sequence similarity, and are not structurally homologous. Such diversity has hindered identification of known or expected UDG-inhibitory activities in other genomes. The structural basis for UDG inhibition by ugi is well characterized; yet, paradoxically, the structure of the unbound p56 protein is enigmatically unrevealing of its mechanism. To resolve this conundrum, we determined the structure of a p56 dimer bound to UDG. A helix from one of the subunits of p56 occupies the UDG DNA-binding cleft, whereas the dimer interface forms a hydrophobic box to trap a mechanistically important UDG residue. Surprisingly, these p56 inhibitory elements are unexpectedly analogous to features used by ugi despite profound architectural disparity. Contacts from B-DNA to UDG are mimicked by residues of the p56 helix, echoing the role of ugi’s inhibitory beta strand. Using mutagenesis, we propose that DNA mimicry by p56 is a targeting and specificity mechanism supporting tight inhibition via hydrophobic sequestration

Is upper gastrointestinal radiography a cost-effective alternative to a Helicobacter pylori “Test and Treat” strategy for patients with suspected peptic ulcer disease?

Current clinical consensus supports an initial Helicobacter pylori (HP) “test and treat” approach when compared to immediate endoscopy for patients with suspected peptic ulcer disease. Alternative diagnostic approaches that incorporate upper GI radiography (UGI) have not been previously evaluated. We sought to determine the cost effectiveness of UGI compared to a HP test and treat strategy, incorporating recent data addressing the reduced prevalence of HP, lower cost of diagnostic interventions, and reduced attribution of PUD to HP. METHODS : Using decision analysis, three diagnostic and treatment strategies were evaluated: 1) Test and Treat —initial HP serology, treat patients who test positive with HP eradication and antiulcer therapy; 2) Initial UGI series —treat all patients with documented ulcer disease with HP eradication and antiulcer therapy; and 3) Initial UGI series, HP serology if ulcer present — treat ulcer and HP based on diagnostic test results. RESULTS : The estimated cost per ulcer cured for each strategy were as follows: test and treat, $3,025; initial UGI,$3,690; and UGI with serology, $3,790. The estimated cost per patient treatment were: test and treat,$498; initial UGI, $610; and UGI with serology,$620. When UGI reimbursement was decreased to less than $50, the UGI strategies yielded a lower cost per patient treated than the test and treat strategy. CONCLUSION : At the current level of reimbursement, UGI should not be considered a cost-effective alternative to the HP test and treat strategy for the initial evaluation of patients with suspected peptic ulcer disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73722/1/j.1572-0241.2000.01837.x.pd

Contrasting Distributions of Urban Green Infrastructure across Social and Ethno-racial Groups

Links between urban green infrastructure (UGI) and public health benefits are becoming well established. Despite this, how UGI is distributed varies widely. Although not a universal finding, sectors of society that are disadvantaged often suffer from poor provision, something which might be due to which UGI are examined. We assess the distribution of street trees and public greenspaces (two types of publicly-owned and accessible UGI) across the city of Bradford, UK which is characterised by high levels of inequality and variation in ethno-racial background. We do this through statistical and spatial analyses. Street tree density was distributed unevenly and was highest in neighbourhoods with a high proportion of Asian/Asian British residents and with lower socio-economic status. Conversely, neighbourhoods with better access to public greenspaces were characterised by high income and/or a high proportion of White households. While the quality of public greenspace was spatially clustered, there were only limited spatial associations with ethno-racial group or socio-economic status. Population density was a key determinant of the distribution of UGI, suggesting understanding UGI distributions should also focus on urban form. Nevertheless, within the same city we show that equitable distribution of UGI differs according to the form and characteristics of UGI. To fully realise the public health benefits of UGI, it is necessary to map provision and understand the causal drivers of unequal distributions. This would facilitate interventions that promote equitable distributions of UGI based on the needs of the target populations

Age and Alarm Symptoms Predict Upper Gastrointestinal Malignancy Among Patients with Dyspepsia

Background: Upper gastrointestinal (UGI) Malignancy is one of the major causes of cancer related death. Endoscopy in dyspeptic patients above 45 years, or those with alarm symptoms may detect this condition. There were only limited data in Indonesia about age and alarm symptoms to predict UGI Malignancy. This study was aimed to determine the prevalence of UGI Malignancy among dyspepsia patients and to develop a simple clinical prediction model.Method: A cross-sectional study to 390 patients with dyspepsia underwent endoscopy in Endoscopy Unit of Sanglah Hospital Denpasar between July 2012 and June 2013 was conducted. Demography and alarm symptoms were documented. Chi-square and logistic regression test analysis were conducted to analyze variables associated with UGI Malignancy.Results: Twenty (5.13%) of 390 patients with dyspepsia had UGI Malignancy. Of the 20 patients, 65% were gastric cancer and 30% were esophageal cancer. The mean age was 59 ± 12 years. Variables associated with UGI Malignancy were weight loss (OR = 8.2), dysphagia (OR = 6.2), age &gt; 45 years old (OR = 5.6), gastrointestinal bleeding (OR = 5.5), persistent vomiting (OR = 5.4), and anemia (OR = 4.9). Using a simplified rule of age &gt;45 years and the presence of any alarm symptom, sensitivity was 85% and specificity was 67.57%.Conclusions: UGI Malignancy was found in 5.13% of patients with dyspepsia who underwent endoscopy. Simple clinical prediction model states that age above 45 years and alarm symptoms may be used as a screening tool to predict UGI Malignancy

Antibiotic use during pregnancy and neurodevelopmental outcomes of offspring in early childhood

There is limited research on the effects of antibiotic use during pregnancy on neurodevelopmental outcomes of offspring in early childhood. The aim of this study was to investigate associations between antibiotic use during early pregnancy and neurodevelopmental outcomes, both behavioral and cognitive, in the offspring during early childhood. This thesis examined a longitudinal study of 570 mother-child pairs where prenatal exposures and at least one neurodevelopment outcome assessment were recorded. An interview was conducted with mothers on average one year after delivery to collect information on prenatal exposures. Neurodevelopmental outcomes were assessed between the ages 5–11 years using the cognitive-based outcomes of Peabody Picture Vocabulary Test (PPVT-III) and the Beery-Buktenica Test of Visual Motor Integration-Fifth Edition (VMI-5) and behavioral-based outcomes of the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF). Adjusted mean differences (adjMD) in outcome measures were calculated between mothers reporting antibiotics use and mothers reporting treated infections. Antibiotic use during pregnancy was not significantly associated with the two cognitive measures but was associated with increased total behavioral problems reported by mothers (adjMD: 2.60; CI: 0.50, 4.69) and teachers (adjMD 2.60; 95% CI 0.44, 4.76). Overall, antibiotics use during pregnancy was not associated with differences in childhood cognition but may be associated with greater behavior problems

Ugi multicomponent reaction to prepare peptide–peptoid hybrid structures with diverse chemical functionalities

Monodisperse sequenced peptides and peptoids present unique nano-structures based on their self-assembled secondary and tertiary structures. However, the generation of peptide and peptoid hybrid oligomers in a sequence-defined manner via Ugi multicomponent reaction has not yet been studied. Herein, we report a synthetic strategy that enables both the modification of peptides as well as the generation of sequence-defined peptide–peptoid hybrid structures. Our synthetic methodology rests on the fusion of solid phase peptide synthesis with Ugi multicomponent reactions. We evidence that a diversity of chemical functionalities can be inserted into peptides or used in the design of peptide–peptoid hybrids exploiting a wide functional array including amines, carboxylic acids, hydrocarbons, carbohydrates as well as polymers, introducing a sequence-defined synthetic platform technology for precision peptoid hybrids